The role of IL-33 in gut mucosal inflammation

Abstract

Interleukin (IL)-33 is a recently identified cytokine belonging to the IL-1 family that is widely expressed throughout the body and has the ability to induce Th2 immune responses. In addition, IL-33 plays a key role in promoting host defenses against parasites through the expansion of a novel population of innate lymphoid cells. In recent years, a growing body of evidence has shown that the proinflammatory properties displayed by IL-33 are detrimental in several experimental models of inflammation; in others, however, IL-33 appears to have protective functions. In 2010, four different research groups consistently described the upregulation of IL-33 in patients with inflammatory bowel disease (IBD). Animal models of IBD were subsequently utilized in order to mechanistically determine the precise role of IL-33 in chronic intestinal inflammation, without, however, reaching conclusive evidence demonstrating whether IL-33 is pathogenic or protective. Indeed, data generated from these studies suggest that IL-33 may possess dichotomous functions, enhancing inflammatory responses on one hand and promoting epithelial integrity on the other. This review focuses on the available data regarding IL-33/ST2 in the physiological and inflammatory states of the gut in order to speculate on the possible roles of this novel IL-1 family member in intestinal inflammation.

Figure 1

IL-33 isoforms and their associated bioactivity. IL-33 is synthesized as a 30 kD protein (full-length-IL-33, f-IL-33); however, alternative splicing can generate a 25 kD peptide (splice-IL-33, spIL-33), which possesses similar bioactivity to f-IL-33, but lacks caspase cleavage sites. During cellular apoptosis, f-IL-33 serves as a potential substrate for pro-apoptotic caspases (caspase-3 and caspase-7), generating smaller peptides of 20–22 kD with a marked reduction in bioactivity. Conversely, when secreted extracellularly, the proinflammatory activity of f-IL-33 may be potentiated in the context of a permissive, proinflammatory environment. In fact, Cathepsin G and elastase, released extracellularly by degranulating neutrophils, are able to cleave f-IL-33 into smaller isoforms (mature-IL-33, m-IL-33, 18–22 kD), which have been reported to display the greatest bioactivity.

Figure 2

Role of IL-33 in murine models of intestinal inflammation. Experimental results obtained from SAMP mice that develop spontaneous Th1/Th2-driven enteritis suggest a pathogenic role for IL-33 at the onset of intestinal inflammation in this specific model. In fact, epithelial-derived IL-33 promotes the release of proinflammatory cytokines from LP immune cells, enhancing both Th1 and Th2 responses. Moreover, IL-33 induces the production of eotaxin-1 and eotaxin-2, which leads to eosinophil chemotaxis to the inflamed gut. In addition, IL-33 activates the expression of profibrotic genes, contributing to the development of intestinal fibrosis (upper panel). Different results are observed in chemically induced models of intestinal inflammation (middle and lower panels). During the onset of acute DSS-induced colitis, IL-33, likely released by necrotic/damaged epithelial cells, participates in the development of intestinal inflammation with a potent chemotactic effect on neutrophils, cells that play a pivotal role in this specific model of colitis (middle panel). Conversely, during the recovery phase of chronic DSS colitis, IL-33 appears to promote wound healing, inducing the restoration of epithelial barrier integrity. On the contrary, when IL-33 is administered to mice displaying a TNBS-induced colitis, which is mainly driven by a Th1 immune response, IL-33 shows an anti-inflammatory effect as a result of the skewing towards a Th2 immunophenotype and the potential induction of T regulatory cell activation (lower panel).